Project Summary/Abstract Enamel is the outer covering of teeth and is unique in that it is the hardest tissue in our body and one of the few human tissues that cannot regenerate. This inability for human enamel to regenerate is attributed to the loss of ameloblasts or enamel-forming cells and their precursor cells upon eruption of teeth into the oral cavity. Thus, it would be powerful if we could direct adult stem cells that normally do not generate enamel to make ameloblasts and unravel the molecular mechanisms involved. I have generated a mouse model that can be induced to produce ectopic ameloblasts from non-enamel forming, adult stem cells with spatial- and temporal- specific inactivation of a gene called Islet1 (Isl1). The identification of ISL1 target genes and genetic networks will reveal new pathways for investigation into numerous questions regarding enamel formation or amelogenesis. A comprehensive molecular understanding of amelogenesis is important for potential future innovations and improvements to current diagnostic, preventive, and therapeutic methods in dentistry.